Mechanistic insights into chemopreventive effects of phenethyl isothiocyanate in N-nitrosobis(2-oxopropyl)amine-treated hamsters.
The influence of phenethyl isothiocyanate (PEITC) on cell kinetics in the target organs of N-nitrosobis(2-oxopropyl)amine (BOP) tumorigenicity and on xenobiotic-metabolizing enzymes was investigated in hamsters. Female 5-week-old Syrian hamsters were given a single s.c. dose of 0, 20 or 50 mg/kg of BOP 2 h after receiving PEITC by gavage at a dose of 0, 100 or 250 mumol/animal (0, 16.3 or 40.8 mg/animal). Six and 22 h after the BOP administration, hamsters were killed and tissues were sampled. Proliferating cell nuclear antigen immunohistochemistry demonstrated significant reduction (P < 0.05-0.001) by PEITC of the labeling indices in the pancreatic acini and ducts, bronchioles, and renal tubules of the BOP-treated animals in a dose-dependent manner. In the lungs, the PEITC pretreatment significantly (P < 0.001) reduced the O6-methyldeoxyguanosine levels as compared to the BOP-alone value. Immunoblot analysis of liver cytochrome P450 isoenzymes showed CYP 2B1 to be mainly involved in the metabolic activation of BOP. PEITC significantly (P < 0.05) inhibited the induction of several isoenzymes, including CYP 2B1, while lowering the hepatic glutathione S-transferase activity as well as glutathione levels, regardless of BOP administration. Our results thus suggest that PEITC exerts its chemopreventive activity against BOP initiation of carcinogenesis in hamsters by decreasing cell turnover and DNA methylation in the target organs, and by influencing hepatic xenobiotic-metabolizing phase I enzymes, although the relationship, if any, of the latter with the former events remains to be investigated.
Nishikawa
A
A
Division of Pathology, National Institute of Health Sciences, Tokyo.
Lee
I S
IS
Uneyama
C
C
Furukawa
F
F
Kim
H C
HC
Kasahara
K
K
Huh
N
N
Takahashi
M
M
D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000378:metabolism; D002273:Carcinogens; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors* / Q000187:drug effects; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D017879:Isothiocyanates / Q000008:administration & dosage* / Q000494:pharmacology; D008647:Mesocricetus; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D009602:Nitrosamines; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*
D016588:Anticarcinogenic Agents; D000951:Antigens, Neoplasm; D002273:Carcinogens; D017879:Isothiocyanates; D009602:Nitrosamines; D018809:Proliferating Cell Nuclear Antigen; C013622:nitrosobis(2-oxopropyl)amine; C058305:phenethyl isothiocyanate; D019362:Cytochrome P-450 CYP2B1; D005982:Glutathione Transferase